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Published on: September 3, 2013
mda-7/IL-24 differentially regulates soluble and nuclear clusterin in prostate cancer
Sujit K Bhutia1, Swadesh K Das, Timothy P Kegelman
1Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, USA.
Abstract:
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24), a unique member of the IL-10 gene family, displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis, and modulation of anti-tumor immune responses. Here, we identify clusterin (CLU) as a MDA-7/IL-24 interacting protein in DU-145 cells and investigate the role of MDA-7/IL-24 in regulating CLU expression and mediating the antitumor properties of mda-7/IL-24 in prostate cancer. Ad.mda-7 decreased expression of soluble CLU (sCLU) and increased expression of nuclear CLU (nCLU). In the initial phase of Ad.mda-7 infection sCLU expression increased and CLU interacted with MDA-7/IL-24 producing a cytoprotective effect. Infection of stable clones of DU-145 prostate cancer cells expressing sCLU with Ad.mda-7 resulted in generation of nCLU that correlated with decreased cell viability and increased apoptosis. In the presence of mda-7/IL-24, sCLU-DU-145 cells displayed G(2)/M phase arrest followed by apoptosis. Similarly, Ad.mda-7 infection decreased cell migration by altering cytoskeleton in sCLU-DU-145 cells. Ad.mda-7-treated sCLU-DU-145 cells displayed a significant reduction in tumor growth in mouse xenograft models and reduced angiogenesis when compared to the vector control group. Tumor tissue lysates demonstrated enhanced nCLU generated from sCLU with increased apoptosis in the presence of MDA-7/IL-24. Our findings reveal novel aspects relative to the role of sCLU/nCLU in regulating the anticancer properties of MDA-7/IL-24 that may be exploited for developing enhanced therapies for prostate cancer.
Insights
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) interacts with clusterin (CLU) to inhibit prostate cancer growth. This interaction promotes apoptosis and reduces tumor progression, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a cytokine with potent antitumor properties.
- Clusterin (CLU) is a secreted and nuclear protein implicated in various cellular processes, including cancer progression and apoptosis.
Purpose of the Study:
- To identify proteins interacting with mda-7/IL-24 in prostate cancer cells.
- To investigate the role of mda-7/IL-24 in regulating CLU expression and its impact on prostate cancer.
- To explore the therapeutic potential of the mda-7/IL-24-CLU interaction in prostate cancer treatment.
Main Methods:
- DU-145 prostate cancer cells were infected with adenovirus expressing mda-7/IL-24 (Ad.mda-7).
- Interaction between mda-7/IL-24 and CLU was assessed.
- Expression levels of soluble CLU (sCLU) and nuclear CLU (nCLU) were analyzed.
- Cell viability, apoptosis, cell migration, and cell cycle were evaluated.
- Prostate cancer xenograft models in mice were used to assess tumor growth and angiogenesis.
Main Results:
- Clusterin (CLU) was identified as an interacting protein with mda-7/IL-24.
- Ad.mda-7 infection modulated CLU expression, decreasing soluble CLU (sCLU) and increasing nuclear CLU (nCLU).
- The mda-7/IL-24-induced conversion of sCLU to nCLU correlated with decreased cell viability, G2/M phase arrest, increased apoptosis, and reduced cell migration.
- Ad.mda-7 treatment significantly reduced tumor growth and angiogenesis in vivo.
- Increased apoptosis was observed in tumor tissues, linked to enhanced nCLU from sCLU.
Conclusions:
- MDA-7/IL-24 interacts with CLU, modulating its expression and subcellular localization.
- The conversion of sCLU to nCLU mediated by MDA-7/IL-24 is crucial for its anticancer effects in prostate cancer.
- These findings reveal novel mechanisms of MDA-7/IL-24 action and suggest potential for targeted prostate cancer therapies exploiting the sCLU/nCLU axis.
